This invention relates to quinoline derivative anti-bacterials.
Kaminsky, in U.S. Pat. No. 3,287,458, discloses anti-bacterial 6,7-methylenedioxy-1,4-dihydro-4-oxo-quinolinecarboxylic acids substituted in the 1 position with lower alkyl or a variety of other substituents. The compound where this substituent is ethyl is commonly known as oxolinic acid.
Oxolinic acid is a highly effective antibacterial agent, but a high incidence of undesirable side effects is reported. Cox, Claire E., Delaware Medical Journal, November 1970, p. 327. And Kershaw and Leigh (Journal of Antimicrobial Therapy 1, 311-315, 1975) have indicated that because of toxicity, "it should not be used as a first-line drug in the therapy of urinary tract infections."
Another quinoline derivative which is now marketed for the treatment of urinary tract infections is nalidixic acid. It was originally shown to be effective for this use; however, further experience with nalidixic acid has suggested that its usefulness may be limited by its tendency to rapidly evoke bacterial resistance. Ronald, A. R. et al. New England Journal of Medicine, 275: 1081-1088 (1966). Moreover, a relatively high incidence of side effects also occurs with nalidixic acid administration. Cox, p. 327.
The compounds of the present invention are also highly effective antibacterial agents; but, unlike the prior art compounds, they do not produce undesirable side effects:
In the general pharmacology screen oxolinic acid produced ataxia, anorexia, excitation, and irritability and nalidixic acid produced some ataxia, and anorexia; whereas the compounds of this invention produced none of these untoward effects. (Tables 3 and 4)